ATLANTIC: Activity landscapes of tumor cell lines determine drug responses

Analysis of cancer cell line (CCL) genomes, proteomes and phenotypic drug responses are emerging approaches to uncover molecular mechanisms of drug action. We extended this paradigm to measuring proteome activity landscapes by integrating quantitative data for 10,000 proteins and 55,000 phosphorylation sites from 125 CCLs with large drug sensitivity data collections. To engage the scientific community in mining the thousands of novel functional associations generated by this work, we provide an interactive web resource termed ATLANTIC (http://atlantic.proteomics.wzw.tum.de). For instance, we found that Progesterone Receptor (PGR) phosphorylation is a stronger drug response predictor than PGR expression alone in hormone receptor positive breast cancer patients. We also demonstrate that Adenylate kinase isoenzyme 1 (AK1) inactivates chemotherapeutic drugs such as Cytarabine. Consequently, high AK1 levels correlated with poor survival of Cytarabine-treated acute myelogenous leukemia patients qualifying AK1 as a treatment stratification and drug response marker and possibly as a drug target.

对癌细胞系（cancer cell line, CCL）的基因组、蛋白质组及药物表型响应开展分析，是揭示药物作用分子机制的新兴研究路径。本研究将该研究范式拓展至蛋白质组活性谱的测定工作中，整合了来自125株癌细胞系的10000种蛋白质与55000个磷酸化位点的定量数据，以及大规模药物敏感性数据集。为助力科研群体挖掘本研究产生的数千条全新功能关联，我们上线了一款命名为ATLANTIC的交互式网络资源（http://atlantic.proteomics.wzw.tum.de）。例如，我们发现，在激素受体阳性乳腺癌患者群体中，孕激素受体（progesterone receptor, PGR）的磷酸化水平相较于单纯的PGR表达量，是更具说服力的药物响应预测因子。此外，本研究还证实，腺苷酸激酶同工酶1（adenylate kinase isoenzyme 1, AK1）可使阿糖胞苷（Cytarabine）等化疗药物失活。因此，在接受阿糖胞苷治疗的急性髓系白血病患者中，高AK1表达水平与不良生存期呈显著相关，这提示AK1可作为治疗分层、药物响应标志物，同时也有望成为潜在的药物靶点。